(1) Field of the Invention
During the study of limonene as a hand cleaner, the applicants found that fully oxygenated limonene is a fungicide. A review of the literature revealed that oxygenated limonene contains several oxidation products including: limonene-1,2-oxide, limonene-8,9-oxide, 1-menthene-9-al, a-2,8-p-menthadiene-1-ol, .beta.-2,8-p-menthadiene-1-ol, dihydrocarvone, .beta.-cymenol, carvone, cis-carveol, and trans-carveol, as was outlined by Bain in U.S. Pat. Nos. 2,863,882 and 3,014,047. Blumann listed the compounds formed by the auto-oxidation of limonene in Chemical Abstracts, Volume 63, 1965, on page 1819, which included cis-carveol, trans-carveol, trans-p-menth-8-ene-1,2-diol, limonene 1,2-epoxide, limonene 8,9-epoxide, cis and trans-p-mentha-2,8-dien-1-ol, and perillyl alcohol. Even though it was unexpected, the applicants found that effective concentrations of dihydrocarveol kill yeast and fungicidal concentrations of dihydrocarveol kill fungi.
Dihydrocarveol is a monocyclic monoterpene with the following chemical formula: ##STR1##
Dihydrocarveol is an oil with a terpenic aroma. It is insoluble in water and glycerine. Dihydrocarveol is soluble in alcohol and is miscible in corn oil, olive oil, and soybean oil, etc. Dihydrocarveol has been used as a bactericide, but heretofore, it has never been known to kill yeast nor fungi.
Bain (in U.S. Pat. No.2,803,647) showed his method of producing carveol and dihydrocarveol and their esters. Leffingwell (in U.S. Pat. No. 3,538,164) produced dihydrocarveol from limonene-1,2-epoxide by the addition of small amounts of perchloric acid. In the Indian Journal of Chemistry 1975, 13(11), 1239-40, Misra showed how to make carveol and dihydrocarveol from carvone.
(2) Description of the Prior Art
Zukerman studied the effect of auto-oxidized limonene on bacteria. He found it was weakly bacteriostatic, was unstable, and that it lost its bacteriostatic effect on keeping as was discussed in Nature 168: 517 (1951). He never studied oxidized limonene nor dihydrocarveol for fungicidal activity. Kurita investigated the fungicidal activity of several components of essential oils in Biol. Chem.. 45(4), 945-952, 1981, and noted that cineole, anethole, safrole, d-limonene, .alpha.-pinene, .beta.-pinene, camphene, .beta.-myrcene, caryophyllene, .beta.-cymene, d-camphor, benzaldehyde, vanillin, and furfural are not fungicidal while cinnamaldehyde, phenol, perillyl aldehyde, citral, perillyl alcohol, geraniol, citronellol, 1-nonanol, 1-deconal, 1-menthol and borneol have minimal to good fungicidal activity. He never studied the anti-yeast or anti-fungal activity of dihydrocarveol. Peter Tetenyi et al studied essential oils obtained from twelve different specimens of Tanacetum vulgare L. and found eight of the twelve specimens to be bactericidal in a concentration of 100 ug/ml against 85-90% of nineteen different bacteria and 100% fungicidal against sixteen species of fungi in a concentration of 50 ug/ml. He delineated numerous chemical components in the oils but he never studied dihydrocarveol or any of the individual components in the oils for anti-bacterial, anti-yeast and/or anti-fungal activity as was outlined in Herba Hungarica, 1981, Tom 20, No. 1-2, pages 57-74. In the Botanical Gazette 122, 194-8 (1961), R. C. French showed that dihydrocarveol stimulates the germination of wheat stem rust uredospores suggesting that dihydrocarveol promotes the growth of fungi. J. C. Maruzzella and L. Liguori reported the in vitro anti-fungal activity of essential oils in the Journal of the American Pharmaceutical Association, Vol. XLVII, No. 4, April 1958, pages 250-4, but they did not study the fungicidal activity of dihydrocarveol. J. C. Maruzzella and Jerry Balter showed the action of essential oils on phytopathogenic fungi in the Plant Disease Reporter Vol. 43, No. 11, Nov. 1959, pages 1143-1147, but they did not study the anti-yeast or the anti-fungal activity of dihydrocarveol. Gauvreau showed a means of producing disinfecting compositions in U.S. Pat. No. 3,595,975 by combining cetyl pyridinium with terpenes to form antiseptics. Gauvreau never studied the use of dihydrocarveol alone nor in combination with cetyl pyridinium. Chastain and Sanders discovered a method of making limonene bactericidal and fungicidal as was described in U.S. Pat. No. 5,153,229, but they never studied dihydrocarveol for bactericidal nor fungicidal activity. A. Morel revealed the sterilizing action of carveol, dihydrocarveol, and their ozonization products in Comp. Rend. Soc. Biol. Volume 115, pages 536-8 (1934). He demonstrated the bactericidal activity of carveol and dihydrocarveol but he never studied their anti-yeast or anti-fungal activity. D. D. Whitehead in U.S. Pat. No. 3,743,747 showed the fungicidal activity of several oxo-derivatives of limonene and dipentene, but he never studied the anti-yeast or anti-fungal activity of dihydrocarveol. J. C. Maruzzella et al reported the action of odoriferous organic chemicals and essential oils on wood-destroying fungi in the Plant Disease Reporter Vol 44, No. 10 (1960); dihydrocarveol was never studied. Murdock and Allen showed the germicidal effect of sodium benzoate against yeast is enhanced by orange peel oil and d-limonene (stripper oil), as was reported in Food Technology, Vol 14, No. 9, 1960, pages 441-5. They never studied the action of dihydrocarveol against yeast or fungi. Kellner et al studied ethereal oils for antimicrobial activity, but they never studied the oils nor any of their chemical constituents for anti-yeast or anti-fungal activity as was outlined in Arzneimittel-Forschung 5, 224-9 (1955).
It should be pointed out that the drugs which are bactericidal are usually not fungicidal, and drugs which are fungicidal are usually not bactericidal. In humans, the use of bactericidal antibiotics frequently promotes the growth of yeast. Table A, which follows, exemplifies the anti-bacterial, anti-yeast and anti-fungal activity of several commonly used anti-bacterial, anti-yeast, and anti-fungal antibiotics.
TABLE A __________________________________________________________________________ ANTIBIOTIC ACTIVITY AGAINST ANTIBIOTICS Gm + Bact Gm - Bact A F Bact Yeast Fungi __________________________________________________________________________ A. ANTIBACTERIAL 1. Ampicillin YES YES NO NO NO 2. Cephalothin YES YES NO NO NO 3. Chloramphenicol YES YES NO NO NO 4. Erythromycin YES NO NO NO NO 5. Ethambutol NO NO YES NO NO 6. Gentamicin YES YES NO NO NO 7. Isoniazid NO NO YES NO NO 8. Nitrofurantoin NO YES NO NO NO 9. Penicillin YES NO NO NO NO 10. Rifampin YES NO YES NO NO Streptomycin YES YES YES NO NO Sulfonamides NO YES NO NO NO Tetracycline YES YES NO NO NO Vancomycin YES YES NO NO NO B. ANTIYEAST 1. Nystatin NO NO NO YES NO 2. Gentian Violet NO NO NO YES NO C. ANTIFUNGAL 1. Chlotrimazole NO NO NO YES YES 2. Griseofulvin NO NO NO NO YES __________________________________________________________________________ Gm + Bact = Gram Positive Bacteria, Gm - Bact = Gram Negative Bacteria, A F Bact = Acid Fast Bacteria, YES = Kills Organism, NO = No Activity Against Organism
It should be noted in the table above that none of the anti-bacterial antibiotics kill yeast nor fungi, and none of the anti-yeast nor anti-fungal antibiotics kill bacteria. Thus an anti-fungal or anti-yeast antibiotic is not expected to kill bacteria, and an anti-bacterial antibiotic is not expected to kill yeast or fungi. Anti-fungal antibiotics do not necessarily kill yeast, and anti-yeast antibiotics do not necessarily kill fungi.
Several differences between yeast and fungi are known and are listed. For instance: (1) yeast can be grown in a culture in 24-48 hours while a fungus requires 7-14 days to grow in a culture. (2) Yeast grow on blood agar while fungi grow on sabouraud dextrose agar. (3) The use of anti-bacterial antibiotics in humans promotes the grow of yeast but the use of anti-bacterial antibiotics in humans does not promote the growth of fungi. (4) Several anti-yeast antibiotics do not kill fungi and several anti-fungal antibiotics do not kill yeast.